Cholesterol Triggers Androgenic Axis Transactivation in CRPC

Cholesterol plays a role in modulating intratumoral androgenic signaling in prostate cancer, but the molecular mechanisms that affect these changes in castration-resistant prostate cancer (CRPC) are not fully understood. A team of researchers from the University of São Paulo Medical School examined the effect of cholesterol on androgen receptor (AR) coactivators expression and tumorigenesis for CRPC both in vitro and in vivo.

The team monitored the expression of genes from AR coactivators SRC-1, 2, 3 and PCAF in PC-3 cells that were exposed to 2 µg/mL of cholesterol for 8 hours by quantitative polymerase chain reaction. Cell migration was performed at 0, 8, 24, 48, and 72 hours, and flow cytometry assays, including viability, apoptosis, and cell cycle were performed after a 24-hour exposure. Immunofluorescence assays were performed to evaluate the protein expression of the AR coactivators.

Additionally, in vivo experiments were carried out on a group of 22 male non-obese diabetic/severe combined immunodeficiency test mice. The mice were subcutaneously implanted with PC-3 cells, and tumor volume was measured every 2 days. After 4 weeks, the tumors were resected and weighed, and the serum lipid profile was measured along with the intratumoral lipid profile and gene and protein expression. Intratumor testosterone and dihydrotestosterone levels were measured using enzyme-linked immunosorbent assay.

Cholesterol was found to up-regulate the gene expression of coactivators SRC-1, 2, 3 and PCAF, and increased AR expression in PC-3 cells. SRC-1, 2, 3 and PCAF proteins also co-localized in the nucleus of cholesterol-supplemented cells and co-associated with AR. The cholesterol-supplemented PC-3 cells showed increased cell migration and altered cell cycle phases, resulting in changes to proliferation and reduced apoptosis.

In the in vivo model, the hypercholesterolemic group was found to have a significantly higher tumor volume than the control group, as well as higher serum total and intratumoral cholesterol levels, testosterone levels, and dihydrotestosterone concentrations.

The research team’s findings concluded that increased nuclear translocation of coactivators results in the up-regulation of AR gene and protein expression, which can influence tumor progression. Further studies targeting cholesterol-modulated changes in AR coactivator expression should be conducted to provide insight into the molecular mechanisms that are associated with the CRPC phenotype.